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Hindawi BioMed Research International Volume 2018, Article ID 6832685, 12 pages https://doi.org/10.1155/2018/6832685

Review Article The Investigation and Management of in Women Who Wish to Improve or Preserve Fertility

Jin-Jiao Li,1 Jacqueline P. W. Chung,2 Sha Wang,1 Tin-Chiu Li,2 and Hua Duan 1

 Department of Gynecology Minimally Invasive Center, Beijing and Gynecology Hospital, Capital Medical University, Beijing , China Department of Obstetrics & , Prince of Wales Hospital, Chinese University of Hong Kong, Shatin, Hong Kong

Correspondence should be addressed to Hua Duan; [email protected]

Received 9 August 2017; Accepted 18 January 2018; Published 15 March 2018

AcademicEditor:WilliamH.Catherino

Copyright © 2018 Jin-Jiao Li et al. Tis is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Te management of adenomyosis remains a great challenge to practicing gynaecologists. Until recently, hysterectomy has been the only defnitive treatment in women who have completed child bearing. A number of nonsurgical and minimally invasive, fertility- sparing surgical treatment options have recently been developed. Tis review focuses on three aspects of management, namely, (1) newly introduced nonsurgical treatments; (2) management strategies of reproductive failures associated with adenomyosis; and (3) surgical approaches to the management of cystic adenomyoma.

1. Introduction endometrial implants are found within the of the . Te most common and widely accepted theory Adenomyosis is a common benign gynaecological condition involves the downward invagination of the endometrial but its diagnosis and treatment remain a clinical challenge to basalis layer into the myometrium due to either myometrial physicians. Te true incidence of adenomyosis is unknown and the prevalence varies widely due to the lack of a weakness or altered immunologic activity leading to standardized defnition and diagnostic criteria. Te preva- disruption of the endometrial-myometrial interface, also lence from previous retrospective cohort and prospective known as the “junctional zone (JZ)” [12]. Leyendecker et cohort observational studies is summarized in Tables 1 and al. [13] showed that uterine auto-traumatisation and the 2 [1–9]. Adenomyosis also commonly occurs together with initiation of the mechanism of tissue injury and repair . Di Donato et al. [10] showed a prevalence of (TIAR) as the primary cause for adenomyosis development 21.8% in women undergoing surgery for endometriosis. Tey based on their method of “visualization” by transvaginal also showed an association with parous women, increasing (TVS) and cinematographic magnetic resonance age, intensity, and presence of deep infltrating imaging (MRI). Teir group showed the archimetral endometriosis. compression from the neometral contraction at the onset Adenomyosis is best defned by Bird in 1972 as “the of menstruation causes high intrauterine pressure, leading benign invasion of into the myometrium, to rupture of the archimyometrium at cornual angles. Tus, producing a difusely enlarged uterus which microscopically fragments of the basal endometrium are then detached and exhibits ectopic non-neoplastic, endometrial glands and deposited into the myometrial wall where they develop into stroma surrounded by the hypertrophic and hyperplastic endometriotic cysts. In addition, as the basal stromal cells myometrium” [11]. at the fundo-cornual raphe are chronically over stretched, it initiates the TIAR mechanism and development of an 2. Pathogenesis adenomyoma. Other theories include de novo development from embryonic-misplaced pluripotent Mullerian remnants Te exact pathogenesis of adenomyosis remains debatable. or invagination along the intramyometrial lymphatic system Tediagnosisofadenomyosisismadewhenectopic or displaced bone marrow stem cells [14]. 2 BioMed Research International

Table 1: Prevalence of adenomyosis afer hysterectomy specimens for various gynaecological conditions (from retrospective cohort studies).

Vercellini et al. Vavilis et al. Seidman and Parazzini et al. Bergholt et al. Study 1995 [1] 1997 [2] Kjerulf1996 [3] 1997 [4] 2001 [5] Number of cases (�)1334 594 1252 707 549 Adenomyosis (%) 25 20 12–58 21 10–18 Uterine fbroid 23 21 15 Genital prolapse 26 26 30 21 18 30 Cervical cancer 19 18 25 Endometrial cancer 28 16 Ovarian cancer 28 21

3. Diagnosis women between 40 and 50 years of age [14]. is present in up to 40–60% of patients, which may be Histologicalexaminationisthegoldstandardinthediagnosis due to the enlarged endometrial surface area or the increased of adenomyosis, even though the exact histological criteria vascularity of the endometrium [14]. Dysmenorrhea occurs have not been universally agreed. One accepted criterion is in 15–30% of patients, which may be related to the swelling the presence of endometrial tissue more than 2.5 mm below of endometrial tissue within the myometrium or increased the endomyometrial junction or a JZ thickness of more than production of prostaglandin within the myometrium [18]. 12 mm [15]. Te modifcation of the uterine structure may Both the amount of bleeding and degree of pain were range from thickening of the JZ of >12 mm to nodular or showntobesignifcantlycorrelatedwiththedegreeof difuse lesions involving the entire uterus. Tus, adenomyosis myometrial invasion [18]. Other presenting features include is classifed to “difuse adenomyosis” where endometrial chronic , , and the fnding of an deposits are found dispersed within the myometrium or enlarged uterus in an asymptomatic subject. Women with “focal adenomyoma” where the endometrial deposits are adenomyosis had been shown to have a decreased quality of more localized at one site within the uterine wall as a confned life [19], up to 33% of patients may be asymptomatic, and the lesion [14]. diagnosis of up to 30% of patients was only made by histology Apartfromthefndingsoftheseectopicendometrial following a hysterectomy [20]. tissues within the myometrium, smooth muscle changes Tere is also increasing evidence to show an association like hyperplasia are ofen found. Ultrastructural diferences between and adenomyosis [21]. Several mecha- between smooth muscle cells from adenomyosis and normal nisms may be involved, including impairment of sperm uterus were found with myocytes showing cellular hypertro- transport [7], aberrant uterine contractility [22], alterations phy, diferences in cytoplasmic organelles, nuclear structures, of molecules, cell proliferation, apoptosis, and free and intercellular junctions [15]. Te myocytes in adenomyosis radical metabolism [15, 23]. Adenomyosis is also speculated also lack the cyclical changes present in myocytes of the to be a cause of recurrent implantation failure during IVF normal uterus [16]. treatment [24].

4. Cystic Adenomyoma 6. Investigation Rarely, adenomyosis may present as a cystic lesion lined .. Two-Dimensional Ultrasound (USG). Two-dimensional with endometrial tissue and surrounded by myometrial tissue when it is called “cystic adenomyoma.” Juvenile cystic (2D) transabdominal USG may reveal uterine enlargement adenomyoma (JCA) is a subgroup of cystic adenomyoma that or asymmetric thickening of the anterior and posterior commonly occurs in adolescents or women < 30 years of age myometrial walls. However, transabdominal USG is ofen and is not associated with difuse adenomyosis. Takeuchi et not accurate enough in diagnosing adenomyosis as it fails al. [17] proposed the following diagnostic features of juvenile to provide sufcient image resolution for visualization of the cystic adenomyoma (JCA): (1) age < 30 years; (2) cystic myometrium. Terefore, 2D transvaginal USG is ofen the lesion of >1 cm in diameter independent of the uterine lumen frst-line investigation. In a review performed by Reinhold and covered by hypertrophic myometrium on diagnostic et al., it was shown that transvaginal USG had a sensitivity images; and (3) association with severe dysmenorrhea. Tey of 80–86%, specifcity of 50–96%, and an overall accuracy of found that laparoscopic excision of the lesion demonstrated 68–86% in diagnosing difuse adenomyosis [25]. signifcant improvement of dysmenorrhea in these cases. USG features of adenomyosis include the presence of three or more sonographic criteria: heterogeneity, increased 5. Presentations echogenicity, decreased echogenicity, and anechoic lacunae or myometrial cysts [26]. In contrast to uterine fbroids, Te classic presentation of adenomyosis is heavy, painful adenomyoma has a more elliptical shaped lesion with poorly menstrual bleeding, typically occurring in multiparous defned borders, no calcifcations, or edge shadowing. In BioMed Research International 3 21 53 87 28 79 54 90 Prevalence% myometrium > 8 mm or greater on T2 weighted images Defnition of adenomyosis Focal adenomyoma: ill-defned lesions within the Difuse adenomyosis: difuse or irregular JZ thickening cysts, hyperechoic islands, adenomyoma, and irregular JZ Focal adenomyoma: expansions of variable shape and size Difuse adenomyosis: expansion of anterior or posterior JZ of fbroids, parallel shadowing, linear striations, myometrial Asymmetrical myometrial thickening not caused by presence that did not extend over the whole length of the uterine cavity TVS MRI MRI MRI Maximal thickness modality Diagnostic < 36 years 11 years 11 years > < clinic ): infertility patients with no performed �=67 Study characteristics old with fertile partners Table 2: Prevalence of adenomyosis from previous prospective cohort observational studies. laparoscopy done showing endometriosis ginal ultrasound scan; JZ: junctional zone. menorrhagia, all had laparoscopy performed Study group ( � = 160 ): infertility patients with Group II: patients with dysmenorrhea Group I: patients with dysmenorrhea Control group ( Infertility patients presenting with dysmenorrhea or Patients with severe dysmenorrhea with laparoscopy Study subgroup: presence of endometriosis, endometriosis or other pelvic disorder on laparoscopy Consecutive patients attending the general gynaecology � ) 70 26 227 985 Number of patients ( Study de Souza et al. 1995 [6] Kunz et al. 2005 [7] Kissler et al. 2008 [8] Nafalin et al. 2012 [9] MRI: magnetic resonance imaging; TVS: transva 4 BioMed Research International doubtful cases, Doppler sonography may be helpful in that Table 3: Accuracy of TVS and MRI for the noninvasive diagnosis of blood vessels in the case of adenomyoma usually follow their adenomyosis. normal vertical course in the myometrial areas while in the TVS MRI case of uterine fbroid, blood vessels are usually located in the periphery [27]. Sensitivity 72% 77% Sonographic diagnosis of adenomyosis is not always easy Specifcity 81% 89% but the consensus statement and recommendation published Positive likelihood ratio 3.7 6.5 by the MUSA (Morphological Uterus Sonographic Assess- Negative likelihood ratio 0.3 0.2 ment) group on how sonographic features of adenomyosis TVS: transvaginal ultrasound scan; MRI: magnetic resonance imaging. shouldbedescribedandmeasuredshouldhelptoimprove the diagnostic accuracy [28]. showed that there was no signifcant diference in sensitivity .. ree-Dimensional Ultrasound. Tree-dimensional (3D) and specifcity between the two groups. Champaneria et USG improves diagnostic accuracy of adenomyosis as it al. [34] also performed a systematic review comparing test allows better imaging of the JZ [29]. Te JZ is ofen visible accuracy between USG and MRI for the diagnosis of adeno- as a hypoechogenic subendometrial halo which is composed myosis. Teir study fndings are summarized in Table 3. Tey of longitudinal and circular closely packed smooth muscle agreed that both TVS and MRI show high levels of accuracy fbers. Upon 3D USG, adenomyosis is characterized by a for the noninvasive diagnosis of adenomyosis. However, we thickenedorirregularJZ[30].AhmadiandHaghighishowed believeMRImaybeparticularlyusefulintheassessmentof the accuracy of 3D transvaginal USG in the diagnosis of focal adenomyoma and provides important information on adenomyosistobe80%andapositivepredictivevalueof whether surgery should proceed. 95% based on the detection of an irregular JZ on coronal plane [31]. Exacoustos et al. [30] analyzed a total of 72 .. Shear Wave Elastography. A recent study also showed premenopausal patients with 2D and 3D transvaginal USG that using Aixplorer (Supersonic Imagine, France) scan- before hysterectomy. In the study, the histological prevalence ner with application of shear wave elastography during of adenomyosis was 44.4%. Teir group agrees that the transvaginal scanning may improve diagnostic accuracy of coronal section of the uterus obtained by 3D transvaginal adenomyosis [35]. Tis study found that adenomyosis was USG allows accurate evaluation and measurement of the associated with a signifcant increase of the myometrial JZ and its alteration shows good diagnostic accuracy for stifness estimated with shear wave elastography. Further adenomyosis. Tey showed that the presence of myometrial studies are required to verify the clinical usefulness of such cysts was the most specifc 2D transvaginal USG feature with an approach. specifcity of 98% and accuracy of 78% while heterogeneous myometrium was the most sensitive feature with a sensitivity . . Hysterosalpingography. Hysterosalpingography is sel- of 88% and accuracy of 75%. As for 3D transvaginal USG, dom used to diagnose adenomyosis. However, in patients with a JZ diference of more than or equal to 4 mm, JZ undergoing infertility assessment, the occasional fnding of infltration and distortion had a high sensitivity of 88% spiculations measuring 1–4 mm in length, arising from the and the best accuracy of 85% and 82%, respectively. Te endometrium towards the myometrium, or a uterus with the overall accuracy of diagnosing adenomyosis for 2D and 3D “tuba erecta” fnding may be suggestive of adenomyosis [36]. transvaginal USG was 83% and 89%, sensitivity was 75% and 91%, specifcity was 90% and 88%, positive predictive value .. Hysteroscopy. Several hysteroscopic appearances have was 86% and 85%, and negative predictive value was 82% and been found to be associated with adenomyosis, including 92%, respectively. 3D USG also has the advantage of allowing irregular endometrium with endometrial defects or super- storage of the images with subsequent ofine manipulation fcial openings, hypervascularization, strawberry pattern, and interpretation. or cystic haemorrhagic lesions [37]. Nevertheless, there is limited data available on the diagnostic accuracy of these .. Magnetic Resonance Imaging. Magnetic resonance imag- various features. ing (MRI) is the gold standard imaging modality for assessing the JZ in the evaluation of adenomyosis [32]. Te common . . Hysteroscopic and Laparoscopic Myometrial Biopsy. In features of adenomyosis on MRI include (1) thickening of the 1992,McCausland[38]showedthatmyometrialbiopsyis JZ, JZ thickness ≥ 12 mm, or irregular junctional thickness helpful to diagnose adenomyosis. Te study found that the with a diference of >5 mm between the maximum thickness depth of adenomyosis was correlated with the severity of and the minimum thickness, (2) an ill-defned area of low menorrhagia. Of the 90 patients studied, 50 patients had signal intensity in the myometrium on T2-weighted MR normal hysteroscopy in which 55% of them had signifcant images, and (3) islands of ectopic endometrial tissue identi- adenomyosis (greater than 1 mm) when compared to controls fed as punctate foci of high signal intensity on T1-weighted (0.8mm).Inthatstudy,itwassuggestedthatminimalade- image [32–34]. However, MRI is expensive and may not be nomyosis may be treated defnitively by endometrial ablation readily available in every unit. Moreover, Reinhold et al. [33] while deep adenomyosis should be treated by hysterectomy. prospectively studied 119 patients undergoing hysterectomy Tey also showed that endometrial glands lef under a scar and compared fndings between TVS and MRI. Te study couldnotonlybleedandcausepainbutalsohavemalignant BioMed Research International 5 potential. Te authors suggested routine myometrial biopsy Danazol. Danazol is an isoxazol derivative of 12 alpha-ethinyl at the time of operative hysterectomy should be considered. testosterone. It causes a hypogonadic state and thus is widely However, Darwish et al. [39] showed hysteroscopic myome- used for treatment of endometriosis and abnormal uterine trial biopsies using rigid biopsy forceps to be inadequate and bleeding [46]. However, data on its use in adenomyosis did not recommend its use. Popp et al. [40] showed that remains limited. Tis may be due to its unwanted adverse the sensitivity of a single myometrial biopsy in diagnosing efects afer systemic treatment. In 2000, Igarashi et al. [47] adenomyosis ranged from 8 to 18.7%, while the specifcity was reported a novel conservative medical therapy for uterine 100% among 680 biopsy specimens in 68 surgically removed adenomyosis with a danazol-loaded intrauterine device in uterus using automatic cutting needle sampling. Gordts et al. 14 women. During insertion of the danazol-loaded IUD, [41] recommended the use of hysteroscopic guided biopsy for there was complete remission of dysmenorrhea in 9 patients, the diagnosis of adenomyosis using a new device, the Utero- reduction in 4, and no change in 1 patient. Tere was complete Spirotome. It can also be used under ultrasound guidance to remission of hypermenorrhea in 12 patients and no change get access to small cystic adenomyoma lesions. in 2. Nine out of 14 patients also showed reduction in the maximum thickness of the myometrium as measured by . . Laparoscopic Myometrial Biopsy. In a prospective, non- MRI. However, further studies are required to confrm the randomized study conducted by Jeng et al. [42] evaluating 100 clinical usefulness of the treatment. patients with clinical signs and symptoms strongly suggestive of adenomyosis, the sensitivity of myometrial biopsy was Dienogest. Dienogest is a selective synthetic oral progestin 98% and the specifcity 100%; the positive predictive value that combines the pharmacological properties of 17-alpha- was 100% and the negative predictive value 80%, which were and 19 nor-progesterone with pronounced local superior to those of transvaginal sonography, serum CA- efect on endometrial tissue. Dienogest has been shown to 125 determination, or the combination of both. Te group be efective in the treatment of endometriosis associated suggested that laparoscopy-guided myometrial biopsy is a pelvic pain. A prospective clinical trial has shown dienogest valuable tool in the diagnosis of difuse adenomyosis in to be a valuable alternative to depot triptorelin acetate for women presenting with infertility, dysmenorrhea, or chronic treatment of premenopausal pelvic pains in women with pelvic pain. uterine adenomyosis. Te study included a total of 41 patients with adenomyosis with pelvic pain and menorrhagia. Te 7. Management patients were allocated to receive oral dienogest (2 mg/day) or triptorelin acetate (3.75 mg/4 weeks) for 16 weeks. Both As in the case of endometriosis, the management strategy of treatments were highly efective in treatment of dysmenor- adenomyosis depends primarily on the presenting symptom rhea, dyspareunia, and chronic pelvic pain associated with and whether it is associated with reproductive failure. adenomyosis, although triptorelin acetate appeared superior to dienogest in controlling menorrhagia [48]. .. Management of Menstrual Symptoms Levonorgestrel-Releasing Intrauterine Device (LNG-IUD). ... Medical Treatment. Medical treatment for adenomyosis LNG-IUD is an intrauterine device, which release 20 is similar to those given for endometriosis. Apart from micrograms of levonorgestrel per day. It has been shown symptomatic relief, hormonal treatment mainly works by to be an efective treatment for abnormal uterine bleeding. inhibition of ovulation, cessation of menses, improving LNG-IUD acts locally and causes decidualization of the hormonal milieu, and causing decidualization of the the endometrium and adenomyotic deposits. LNG-IUD endometrial deposits. alleviates dysmenorrhea by improving uterine contractility Analgesic. Nonsteroidal anti-infammatory (NSAIDs) and reducing local prostaglandin production within the work by inhibiting the cyclooxygenase (COX-1 and COX-2) endometrium. LNG-IUD appears to be an efective method and decreasing the production of prostaglandins. NSAIDs in relieving dysmenorrhea associated with adenomyosis have been proved to be efective in treatment of primary [49] and more efective than the combined OC pill [50], dysmenorrhea by Gambone et al. [43]. It is usually the frst- improved the quality of life [19], and appears to be a line treatment for symptomatic pain relief for adenomyosis. promising alternative treatment to hysterectomy. LNG-IUD may be used in conjunction with other treat- Oral Contraceptive Pills (OCPs). Combined oral contraceptive ment modalities such as GnRH analogue [51] or transcervical pills work by inhibiting ovulation by suppressing the release resection of the endometrium (TCRE) [52]. In the latter study, of gonadotrophins. Many studies have shown that they are it was found that TCRE combined with LNG-IUD was more efective in the treatment of dysmenorrhea. A prospective efective in reducing menstrual fow compared with the LNG- observational trial showed that continuous low-dose OCP IUD alone although there was no signifcant diference in were more efective than cyclical low-dose OCP in con- theamountofpainreductionbetweenthetwotreatment trolling symptoms in patients afer surgical treatment for strategies. endometriosis [44]. Mansouri et al. [45] have shown regres- sion of adenomyosis on MRI afer using oral contraceptive GnRH Agonists. GnRH agonists are efective in alleviating pills for 3 years in adolescents with adenomyosis presenting dysmenorrhea and relieving menorrhagia associated with chronic pelvic pain. with adenomyosis [53]. However, due to the undesirable 6 BioMed Research International climacteric side efects and risk of osteoporosis, treatment follow-up showed that improvement in dysmenorrhea and with GnRH agonists is usually restricted to a short duration menorrhagia are more likely to occur in vascular lesions of 3–6 months although the duration of use may be [62]. extended if add-back estrogen therapy is employed [54]. Discontinuation of treatment usually leads to regrowth of ... High Intensity Focused Ultrasound. High intensity thelesionsandrecurrenceofsymptoms. focused ultrasound (HIFU) is another nonsurgical treatment for uterine fbroids that focuses high intensity ultrasound in Selective Estrogen Receptor Modulator (SERM).Selective the target lesion causing coagulative necrosis and shrinkage estrogen receptor modulators like tamoxifen or raloxifene of the lesion. Both MRI and USG can be used for guidance have been tried in the treatment of endometriosis [54] based for the procedure. MRI has better real time thermal mapping on observations that SERMs may reduce endometriosis lesion during the HIFU treatment. Yet, ultrasound guided HIFU is in mouse [55]; however, their value in the treatment of less costly and ofers real time anatomic monitoring imaging adenomyoma has not been formally explored. andagreyscalechangeduringtreatmentrepresentsareliable indicator in treatment response. It is efective in both focal Aromatase Inhibitors. Like endometriosis, adenomyotic and difuse lesions [63, 64]. Ultrasound guided HIFU was deposits are estrogen-dependent. Aromatase inhibitors showntobetechnicallysuccessfulinupto94.6%ofpatients inhibit the conversion of estrogen from androgens, in a review of 2549 patients among 10 diferent centers with thereby lowering the synthesis of estrogen. A prospective symptomatic adenomyosis [65]. randomized controlled study found that the efcacy of aromatase inhibitors (letrozole 2.5 mg/day) in reducing the ... Endomyometrial Ablation or Resection. Tere is limited volume of adenomyoma as well as improving adenomyosis report on the use of laparoscopic or hysteroscopic endome- symptoms was similar to that of GnRH agonists (goserelin trial in treating adenomyosis in the literature. Te success 3.6 mg/month) [56]. Kimura et al. also reported on the rate of myometrial electrocoagulation ranges from 55 to 70% combined use of aromatase inhibitors with GnRH agonist as reported [66]. Wood [67] reported success in 4 out of with good results in a 34-year-old woman with severe uterine 7 patients who underwent myometrial electrocoagulation, adenomyosis who wished to preserve fertility [57]. Tey whilePhillipsetal.[68]had7outof10patientswith found a reduction in uterine volume of 60% afer 8 weeks symptomatic adenomyosis diagnosed by MRI treated with of treatment as determined by magnetic resonance imaging laparoscopic bipolar coagulation, having signifcant reduc- and ultrasound. tion or resolution of dysmenorrhea or heavy menstrual bleeding. Ulipristal Acetate. Ulipristal acetate (UPA) is a potent selec- tive progesterone receptor modulator. Tere is good evidence .. . Hysterectomy. Hysterectomy is the defnitive treatment to suggest that it can be used to shrink fbroid and control option for intractable symptomatic adenomyosis when med- menorrhagia [58, 59]. It is possible that it may be similarly ical or other conservative treatments have failed to con- efective in the treatment of adenomyoma but literature data trol the symptoms. Patients undergoing hysterectomy for is lacking. adenomyosis should be advised of an increased risk of bladder injury and persistent pelvic pain. Furuhashi et al. Antiplatelet erapy. Tere is new evidence to suggest a role [69] reviewed 1246 vaginal hysterectomies and found that of antiplatelet therapy in treating adenomyosis. Emerging patients undergoing vaginal hysterectomy for adenomyosis evidence suggests that endometriotic lesions are wounds have increased risk of bladder injury compared with those undergoing repeated tissue injury and repair (ReTIAR), and performed for leiomyoma (2.3% versus 0.7%). It may be a platelets induce epithelial-mesenchymal transition (EMT) result of difculty in identifying the supravaginal septum and fbroblast-to-myofbroblast transdiferentiation (FMT), and the vesicovaginal or vesicocervical planes. Several studies leading ultimately to fbrosis. Adenomyotic lesions are have reported on persistent pelvic pain afer hysterectomy thought to have similar pathogenesis to that of endometriosis. for adenomyosis [70]. Once a decision to proceed with A recent study in mice suggests that antiplatelet treatment hysterectomy has been made, the possibility of oophorectomy may suppress myometrial infltration, improve generalized should be discussed. In general, it is not considered necessary hyperalgesia, and reduce uterine hyperactivity [60]. to routinely remove the ovaries in premenopausal women [71, 72], but it may be indicated in women who sufer from ... Uterine Artery Embolization. Uterine artery embol- cyclical symptoms, with concomitant ovarian endometriosis, ization (UAE) has been used to treat symptomatic fbroids or who are considered to have an increased risk of developing since the 1990s. Tere is increasing evidence to suggest ovarian cancer, including those with a family history of that it is also efective in the treatment of management the condition. Interestingly, a recent population-based study of adenomyosis. In a review of 15 studies including 511 by Kok et al. [73] suggested that the risk of developing women with adenomyosis, Popovic et al. found [61] ovarian cancer in women with newly diagnosed adenomyosis signifcant clinical and symptomatic improvement in is increased by 4-5-fold. If the fnding is confrmed, there seventy-fve percent of subjects at short- and long-term is a strong case to consider prophylactic oophorectomy at follow-up. A recent retrospective observational study of the time of hysterectomy for adenomyosis in premenopausal 252 patients who underwent UAE with up to fve years of women. BioMed Research International 7

.. Reproductive Failure. Several studies have shown that following GnRH analogue suppression therapy, before the adenomyosis is associated with a negative impact on the adenomyosis lesion regrows to its pretreatment size and success rate of IVF. In a recent meta-analysis conducted exerts its adverse impact on implantation, may improve the by Vercellini et al. [74], adenomyosis was associated with a result. 28% reduction in the likelihood of a clinical in infertile women who underwent IVF/ICSI with autologous ... Mock . Performing a mock embryo oocytes. Patients with adenomyosis were found to have transfer is desirable in women with adenomyosis, as it may higher chances of , independent of oocyte or help to assess the uterine cavity length and position, choose embryo quality. Talluri and Tremellen [75] also showed that the correct transfer catheter, and alert the clinicians any extra the adenomyosis was associated with a signifcant reduc- precautions (e.g., use of tenaculum or cervical dilatation). tion in successful implantation of good-quality embryos in Mock embryo transfer is particularly desirable in those with patients undergoing IVF treatment (viable clinical pregnancy an enlarged uterus or distorted uterine cavity. rate 23.6% versus 44.6% among those who did not have adenomyosis, � = 0.017). .. . Single Embryo Transfer. Adenomyosis has been Puente et al. [76] performed a cross-sectional study of reported to be associated with increased incidence of 1015 patients prior to assisted conception treatment. Tey preterm delivery, preeclampsia, and second trimester found that the prevalence of adenomyosis was 24.4% in miscarriage when compared with the control group [81]. women aged ≥40 years and 22% in women aged ≤40 years. Consequently, multiple should be avoided and Te prevalence of adenomyosis was found to be higher in so single embryo transfer should be advised. Women who those with recurrent pregnancy loss (38.2%) and previous had adenomyomectomy prior to IVF should also be advised ARTfailure(34.7%)whencomparedwiththosewhodidnot to have SET to avoid multiple pregnancy with a view to (22.3% and 24.4%, respectively). Tey also found that 4 out minimize the risk of scar rupture. of 5 patients had the diagnosis missed in earlier transvaginal ultrasonography. ... HRT Protocol in Frozen-awed Embryo Transfer (FET) Te use of short-term GnRH agonists to shrink the Cycle. GnRH agonist pretreatment to suppress the pituitary size of the adenomyosis lesion has been shown to improve ovarian axis prior to hormone replacement therapy to pre- conception rate within 6 months of cessation of GnRH pare the endometrium in FET cycles appeared to improve agonist therapy [77, 78]. the outcome compared with hormone replacement therapy In women with adenomyosis planning to undergo IVF without downregulation. In a study including 339 patients treatment, the following management strategies should be with adenomyosis, 194 received long-term GnRH agonist considered. plusHRT(downregulation+HRT)and145withHRT alone. Te clinical pregnancy, implantation, and ongoing ... GnRH Analogue erapy before In Vitro Fertilization. pregnancy rates in the downregulation and HRT group were Several studies have shown that pretreatment with GnRH signifcantly higher than that of the HRT alone group, being analogue before IVF treatment improved pregnancy out- 51.35% versus 24.83%, 32.56% versus 16.07%, and 48.91% come. Zhou et al. [79] analyzed the clinical efcacy of versus 21.38%, respectively [82]. leuprorelin acetate in treatment of uterine adenomyosis with infertility. Tey found that, afer 2–6 months of leuprorelin .. . Uterine Contractility and Atosiban erapy. Several acetate therapy, the mean uterine volume was signifcantly functional studies showed that excessive uterine contractility 3 3 > reduced from 180 ± 73 cm to 86 ± 67 cm ,leadingtoan ( 5 contractions per minute) has been demonstrated in improvement in embryo implantation and clinical pregnancy approximately 30% of patients undergoing embryo transfer rates. and this may have a signifcant adverse impact on subsequent embryo implantation and clinical pregnancy rates [83]. Te ... Stimulation Protocol. In women without pre-IVF incidence of abnormal contractility appeared to be higher in GnRH analogue therapy as described above, long GnRH women with adenomyosis [84] which may in part explain analogue protocol should be considered as it helps to induce the higher incidence of reproductive failure observed in this decidualization of the adenomyotic deposits rendering the group of women. Although recent evidence suggests that the diseaseinactive.Taoetal.[80]showedthatGnRHantagonist routineuseofatosibantherapydoesnotimprovetheoutcome protocol appears to be inferior to GnRH agonist long protocol [85],itispossiblethattheuseofatosibaninaselected cycle, and the latter appeared to be associated with increased group of women with aberrant uterine contractions during pregnancy and decreased miscarriage rates. embryo transfer may improve the outcome. Ideally, women with adenomyosis should be screened for abnormal uterine ... Two-Staged In Vitro Fertilization. In women with contractions during ET; if the results are abnormal atosiban adenomyosis, a two-staged in vitro fertilization could be therapy should be discussed; alternatively, the possibility of considered. Patients can undergo ovarian stimulation, oocyte empirical atosiban therapy in women with adenomyosis and retrieval, and fertilization followed by frozen-thawed embryo recurrent implantation failure could be considered. transfer (FET) at a later stage. Prior to the FET, GnRH analogue suppression therapy for 3 months or so leads to .. . Recurrent Implantation Failure. Recurrent implanta- shrinkage of the adenomyosis. FET in the frst HRT cycle tion failure is diagnosed when there is failure to achieve a 8 BioMed Research International

(a) (b)

Figure 1: (a) Ultrasound and (b) MRI appearance of a cystic adenomyoma. clinical pregnancy afer transfer of at least four good-quality 5 mm between the serosa and adenomyoma is considered embryos in a minimum of three fresh or frozen cycles in necessary to avoid the risk of uterine perforation although a woman under the age of 40 years [86]. It is known that the safety margin may sometimes increase afer part of the adenomyosisisassociatedwithrecurrentimplantationfailure lesion has been removed and the uterine contractions which [24]. Women with recurrent implantation failure should be follow help to push the adenomyoma further towards the ofered 3D scan or MRI to establish if there is adenomyosis; cavity. Pretreatment with 3-month course of GnRH agonist if adenomyosis is present, the above management strategies beforehand can help reduce the vascularity and bleeding should be adopted to improve the outcome. during the operation. Sometimes, it may also help to push the adenomyoma towards the uterine cavity due to the reduction .. . Uterine Sparing Conservative Surgery. Surgery is sel- of uterine volume. dom required for women prior to IVF treatment, the indica- Te location of the adenomyoma should be clearly tion being (1) well-defned adenomyoma more than 5 cm and defned before the start of the procedure. Using a lower (2) recurrent miscarriage or recurrent implantation failure perfusing pressure, say at 40 mmHg instead of the usual afer IVF. A retrospective cohort study performed by Kishi et 90–100 mmHg, may allow a slight bulge of the adenomyoma al. [87] involving 102 women showed that laparoscopic ade- into the cavity to be visualized. Vasopressin, a potent vaso- nomyomectomy was benefcial for women who experienced constrictor, may be injected into the uterus by using an oocyte IVF treatment failures if they were <39 years old but not for retrieval needle [89] to result in contraction of the uterus patients aged 40 years or more. No beneft of uterine sparing and reduce bleeding. Aferwards the endometrium and the surgery is seen for those older patients aged 40 or above. myometrium overlying the adenomyoma can be incised Grimbizis et al. [88] reviewed the current literature and using a cutting loop or needle or dissected with the use of a described three main categories of uterine sparing surgical pair of scissors, following which the adenomyoma is removed treatment, including complete excision by adenomyomec- by the cutting loop or a pair of grasping forceps coupled tomy; cystectomy or partial excision cytoreductive surgery; with twisting actions, separating it from the underlying and nonexcisional techniques including uterine artery lig- myometrium. Te latter step may be achieved with the use ation, electrocoagulation of myometrium, resection, and of Hysteroscopy Endo-Operative System (HEOS) [90], which ablation.Tereviewconcludedthatuterinesparingtreatment allows both mechanical and electrosurgical instruments to be of adenomyosis appears feasible and efective. Afer complete used. Complete removal of the adenomyoma may be difcult. excision, the dysmenorrhea reduction, menorrhagia control, A repeat surgical procedure may be required from time to and were 82.0%, 68.8%, and 60.5%, respec- time. tively. Afer partial excision, the dysmenorrhea reduction Cystic adenomyoma is a special category of adenomy- rate was similar at 81.8%, although menorrhagia control and oma. Figures 1(a) and 1(b) show the ultrasound and MRI pregnancy rate were slightly reduced to 50.0% and 46.9%, appearance of a cystic adenomyoma. At the beginning of the respectively. hysteroscopic operation, the adenomyoma did not appear to bulge into the cavity (Figure 2(a)), but upon lowering .. Hysteroscopic Surgery. Justasitisnowpossibletoremove the perfusing pressure, the cystic adenomyoma was seen intramural myoma with refned hysteroscopic techniques, bulging into the cavity (Figure 2(b)), which permits the hysteroscopic adenomyomectomy may also be possible in precise location of the lesion to be identifed. In this particular selected cases, especially when the adenomyoma is <5cm case, a longitudinal incision was made over the adenomyoma, or when it protrudes into the uterine cavity. However, draining a large amount of blood clots from the cystic hysteroscopic adenomyomectomy should always be carried adenomyoma. In this case, initial attempts to dissect the cystic out under USG guidance. A minimal safety margin of adenomyoma away from the myometrium (Figure 2(c)) had BioMed Research International 9

(a) (b)

(c) (d)

Figure 2: (a) Hysteroscopic view at high perfusion pressure. (b) Hysteroscopic view at low perfusion pressure with bulging of cystic adenoma seen. (c) Hysteroscopic dissection of cystic adenomyoma wall away from endometrium. (d) Roller ball ablation of adenomyotic deposits.

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